EP0484281B2 - Zyklosporine - Google Patents

Zyklosporine Download PDF

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Publication number
EP0484281B2
EP0484281B2 EP91810841A EP91810841A EP0484281B2 EP 0484281 B2 EP0484281 B2 EP 0484281B2 EP 91810841 A EP91810841 A EP 91810841A EP 91810841 A EP91810841 A EP 91810841A EP 0484281 B2 EP0484281 B2 EP 0484281B2
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ciclosporin
meleu
hydroxy
mebmt
meval
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EP0484281A2 (de
EP0484281B1 (de
EP0484281A3 (en
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Soo Young Ko
Hans Kobel
Brigitte Rosenwirth
Dieter Seebach
René P. Traber
Roland Wenger
Pietro Bollinger
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Novartis AG
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Novartis Erfindungen Verwaltungs GmbH
Novartis AG
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Priority claimed from GB909023859A external-priority patent/GB9023859D0/en
Priority claimed from GB909023970A external-priority patent/GB9023970D0/en
Priority claimed from GB909023971A external-priority patent/GB9023971D0/en
Priority claimed from GB909023972A external-priority patent/GB9023972D0/en
Priority claimed from GB919116836A external-priority patent/GB9116836D0/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A61K38/13—Cyclosporins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/10—Anthelmintics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/64—Cyclic peptides containing only normal peptide links
    • C07K7/645—Cyclosporins; Related peptides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S435/00—Chemistry: molecular biology and microbiology
    • Y10S435/8215—Microorganisms
    • Y10S435/911—Microorganisms using fungi
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S930/00—Peptide or protein sequence
    • Y10S930/01—Peptide or protein sequence
    • Y10S930/27—Cyclic peptide or cyclic protein

Definitions

  • the present invention relates to novel cyclosporins, their use as pharmaceuticals and pharmaceutical compositions comprising them, as well as to processes for their production.
  • the cyclosporins comprise a class of structurally distinctive, cyclic, poly-N-methylated undecapeptides, commonly possessing pharmacological, in particular immunosuppressive, anti-inflammatory and/or antiparasitic activity.
  • the first of the cyclosporins to be isolated was the naturally occurring fungal metabolite Ciclosporin or Cyclosporine, also known as cyclosporin A and commercially available under the Registered Trademark SANDIMMUN R or SANDIMMUNE R .
  • Ciclosporin Since the original discovery of Ciclosporin, a wide variety of naturally occurring cyclosporins have been isolated and identified and many further non-natural cyclosporins have been prepared by total- or semi-synthetic means or by the application of modified culture techniques.
  • the class comprised by the cyclosporins is thus now substantial and includes, for example, the naturally occurring cyclosporins A through Z [cf. Traber et al; 1, Helv. Chim. Acta, 60 , 1247-1255 (1977); Traber et al; 2, Helv. Chim. Acta, 65 , 1655-1667 (1982); Kobel et al, Europ. J.
  • cyclosporins in which the MeBmt residue is present in isomeric form e.g. in which the configuration across positions 6' and 7' of the MeBmt residue is cis rather than trans
  • cyclosporins in which variant amino acids are incorporated at specific positions within the peptide sequence e.g. employing the total synthetic method for the production of cyclosporins developed by R. Wenger - see e.g. Traber et al. 1, Traber et al, 2 and Kobel et al., loc.
  • the class comprised by the cyclosporins is thus now very large indeed and includes, for example, [Thr] 2 -, [Val] 2 -, [Nva] 2 - and [Nva] 2 -[Nva] 5 -Ciclosporin (also known as cyclosporins C, D, G and M respectively), [3-O-acetyl-MeBmt] 1 -Ciclosporin (also known as cyclosporin A acetate), [Dihydro-MeBmt] 1 -[Val] 2 -Ciclosporin (also known as dihydro-cyclosporin D), [(D)Ser] 8 -Ciclosporin, [MeIle] 11 -Ciclosporin, [(D)MeVal] 11 -Ciclosporin (also known as cyclosporin H), [MeAla] 6 -Ciclosporin, [(D)Pro] 3 -Ciclosporin and so on.
  • cyclosporins In accordance with conventional nomenclature for cyclosporins, these are defined throughout the present specification and claims by reference to the structure of Ciclosporin (i.e. Cyclosporin A). This is done by first indicating those residues in the molecule which differ from those present in Ciclosporin and then applying the term "Ciclosporin” to characterise the remaining residues which are identical to those present in Ciclosporin. At the same time the prefix "dihydro" is employed to designate cyclosporins wherein the MeBmt residue is hydrogenated (dihydro-MeBmt) i.e. where -x-y- in formula B is -CH 2 -CH 2 -.
  • [Thr] 2 -Ciclosporine is the cyclosporin having the sequence shown in Formula A but in which ⁇ Abu at the 2-position is replaced by Thr
  • [Dihydro-MeBmt] 1 -[Val] 2 -Ciclosporin is the cyclosporin having the sequence shown in Formula A but in which the MeBmt residue at position 1 is hydrogenated and ⁇ Abu at the 2-position is replaced by Val.
  • amino acid residues referred to by abbreviation e.g. Ala, MeVal, ⁇ Abu etc. are, in accordance with conventional practice, to be understood as having the (L)-configuration unless otherwise indicated, e.g. as in the case of "(D)Ala”.
  • Individual residues of the cyclosporin molecule are numbered, as in the art, clockwise and starting with the residue MeBmt or dihydro-MeBmt in position 1. The same numerical sequence is employed throughout the present specification and claims.
  • Ciclosporin acts by interfering with the process of T cell activation by blocking transcription initiation of IL-2, although the precise mechanism has not yet been elucidated. Ciclosporin has been shown to form a complex with a 17kD cytosolic protein (cyclophilin) that occurs in many cell types and has been shown to be identical to peptidyl-prolyl cis-trans isomerase, an enzyme involved in protein folding. Up to now, however, it has not been clear whether binding to cyclophilin is directly correlated with immunosuppressive activity in cyclosporins, or indeed whether cyclophilin binding is itself a sufficient criterion for immunosuppressive activity.
  • cyclophilin 17kD cytosolic protein
  • the present invention provides cyclosporins which are active against HIV-1 replication.
  • HIV Human immune deficiency virus
  • T4 lymphocytes T-helper lymphocytes
  • T4-cell destruction AIDS
  • Other immunological abnormalities of AIDS are increase of cytotoxic/suppressor (T8) lymphocytes, a defect in the antigen presentation/recognition process and polyclonal activation of B-cells.
  • T8 lymphocytes cytotoxic/suppressor lymphocytes
  • the mechanism of T4-cell destruction is still not clear. Relatively few T4-cells seem to be infected, thus, a direct cytopathic effect caused by the virus may not be the only reason for T4-cell depletion.
  • T4-cell destruction could be amplified by an autoimmune process triggered by HIV-producing or HIV-protein-coated T4-cells. This continuous antigenic stimulation may lead to a state of permanent activation of T4-cells which would enhance HIV-replication in these cells and expand T-cytotoxic clones. Uninfected T4-cells may be rendered antigenic by binding exogenous viral gp120 to their CD4 molecules and would thus be a target of a T-cytotoxic response.
  • Ciclosporin has activity against AIDS, and that in general "cyclosporins known as immunosuppressors" may be useful in this indication. There is no suggestion that non-immunosuppressive cyclosporins might be expected to have this property.
  • a cyclosporin is considered as binding to cyclophilin if it binds to human recombinant cyclophilin at least one fifth as well as does Ciclosporin in the competitive ELISA test described by Quesniaux in Eur. J. Immunol. 1987 17 1359-1365.
  • the cyclosporin to be tested is added during the incubation of cyclophilin with coated BSA-Ciclosporin and the concentration required to give a 50% inhibition of the control reaction without competitor is calculated (IC 50 ).
  • the results are expressed as the Binding Ratio (BR), which is the log to the base 10 of the ratio of the IC 50 of the test compound and the IC 50 in a simultaneous test of Ciclosporin itself.
  • BR Binding Ratio
  • a cyclosporin is considered to be non-immunosuppressive when it has an activity in the Mixed Lymphocyte Reaction (MLR) of no more than 5%, preferably no more than 2%, that of Ciclosporin.
  • MLR Mixed Lymphocyte Reaction
  • the Mixed Lymphocyte Reaction is described by T.Meo in "Immunological Methods", L. Lefkovits and B. Peris, Eds., Academic Press, N.Y. pp. 227-239 (1979).
  • Spleen cells (0.5 x 10 6 ) from Balb/c mice (female, 8-10 weeks) are co-incubated for 5 days with 0.5 x 10 6 irradiated (2000 rads) or mitomycin C treated spleen cells from CBA mice (female, 8-10 weeks).
  • the irradiated allogeneic cells induce a proliferative response in the Balb c spleen cells which can be measured by labeled precursor incorporation into the DNA. Since the stimulator cells are irradiated (or mitomycin C treated) they do not respond to the Balb/c cells with proliferation but do retain their antigenicity.
  • the IC 50 found for the test compound in the MLR is compared with that found for Ciclosporin in a parallel experiment.
  • the HTLV-I-transformed T4-cell line, MT4 which was previously shown to be highly permissive for HIV-infection, is used as the target cell.
  • Inhibition of HIV-1, strain HTLV-IIIB-induced cytopathic effect is determined by measuring the viability of both HIV-infected and mock-infected cells. Viability is assessed spectrophotometrically via in situ reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT).
  • MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide
  • Virus-infected and uninfected cultures without compound are included as controls as are uninfected cells treated with compound.
  • the cell concentration is chosen so that the number of cells per ml increases by a factor of 10 during the 4 days of incubation in the mock-infected cultures.
  • Virus inoculum is adjusted so as to cause cell death in 90% of the target cells after 4 days of incubation.
  • the virus is adsorbed onto a 10-fold concentrated cell suspension at 37° C for 1 hour. Then, the infected cells are diluted 1:10 and added to microtiter plates containing the test compound.
  • cellular toxicity of the test compound to these cell lines is first assessed.
  • Jurkat and U937 cell suspensions are adjusted to 1x10 5 cells/ml and incubated in the presence of various concentrations of test compound. After 48 hours the amounts of cells per ml are compared by staining with MTT. Cytoxicity in MT4 cells may be measured in the same way.
  • the T4-cell line Jurkat and the monocytic cell line U937 are infected by suspending the cells 10-fold concentrated in virus solution. Adsorption is allowed for 2 hours at 37° C. The cells are then spun down, the inoculum is removed and the cells are resuspended at their original concentration in fresh culture medium containing test compound. Thus, the substance is added post adsorption. At days 2, 5, 8, 12, 15 and 19 post-infection, aliquots of the infected cultures are removed. Cells are spun down and the supernatants collected. The concentration of viral p24 antigen is determined in the supernatants by means of a commercial ELISA kit and serves as a parameter for virus production. After each removal of aliquots, cells are counted and adjusted to 2x10 5 cells/ml by adding fresh medium containing the test compound at the particular concentration.
  • cyclophilin-binding cyclosporins active against HIV-1 Active Compounds
  • some are novel and others are known; however the anti-HIV activity of the known Active Compounds has not previously been disclosed, and in many cases the known Active Compounds have not been disclosed to have any pharmaceutical activity whatsoever.
  • One group of Active Compounds are cyclosporins in which the MeLeu group at position 4 is replaced by a different N-methylated amino acid, for example ⁇ -hydroxy-MeLeu, MeIle, MeVal, MeThr or MeAla.
  • the allo-forms MeaIle and MeaThr may also be used.
  • the stereochemistry at the ⁇ -position has the opposite configuration to that of the natural amino acid, so that the normal form and the allo-form constitute a pair of diastereoisomers.
  • a further group of Active Compounds is that in which Val at the 5-position is replaced by an N-alkyl-, preferably N-methyl-, amino acid.
  • the amino acid which is N-alkylated is Val or Leu.
  • the hydrogen of the imino group of [Val] 5 is replaced by a non-branched C 1-6 alkyl group, preferably methyl, ethyl or n-propyl, particularly methyl.
  • Active Compounds may differ from Ciclosporin at the 1, 2, 3, and/or S positions.
  • a preferred group of Active Compounds is constituted by the compounds of Formula I: in which
  • One especially preferred group of Active Compounds are the compounds of Formula I in which W is W', X is X', Y is Y', Z is Z', Q is Q' and R is R'.
  • Particularly preferred compounds of Formula I are:
  • the invention also provides novel Active Compounds, which are compounds of Formula II: where W', X, R, Y and Z are as defined above, provided that 1) when Y is MeLeu or MeAla then Z is MeVal or MeLeu and 2) when W' is MeBmt, R is Sar, and Y is ⁇ -hydroxy-MeLeu, then Z is other than Val.
  • a preferred group of novel Active Compounds consists of the compounds of Formula II in which X is X'', Y is Y' and Z is Z', provided that when W' is MeBmt, Y' is other than ⁇ -hydroxy-MeLeu.
  • novel Active Compounds are the compounds a), b), c), d), f) and h) above. Certain of these compounds, for example compounds b) and c), are found to block the immunosuppressive action of Ciclosporin by blocking its binding to cyclophilin, and thus act as Ciclosporin antagonists.
  • the Active Compounds may be obtained in a variety of ways, which may be classified as:
  • Compound k is a known substance whose properties have been described by Quesniaux et al ( Mol. Immunol. 24 1159 1987) and which can also be prepared by total synthesis. For example, a total synthesis of this compound is described in USP 4,914,188.
  • Compound c) is obtained by fermentation of the fungal strain Tolypocladium inflatum Cy E 4556, deposited at the Deutsche Sammlung für Mikroorganismen under the provisions of the Budapest treaty on 24 July 1991 under the accession number DSM 6627.
  • This strain is a mutant of the strain NRRL 8044 of the species Tolypocladium inflatum Gams, and is taxonomically identical with the parent strain, which has been fully described, e.g. in British Patent 1,491,509.
  • Compound e) is obtained from biotransformation of Ciclosporin by the microorganism Sebekia benihana .
  • the original strain used is named NRLL 11111 and belongs to the species Sebekia benihana (Dietz and Li: Sebekia , a new genus of the family Actinoplanaceae. Abstrs. 82nd Ann.Meet.Amer.Soc.Microbiol., 163, Atlanta, 1982). This strain is able to hydroxylate novobiocin.
  • the subcultured strain used for the preparation of compound e and related compounds has been deposited at the German Collection of Microrganisms (D-3300 Braunschweig) under the number DSM 6182.
  • the more polar side fractions originating from the purification of [ ⁇ -hydroxy-MeLeu] 4 -Ciclosporin are further separated by repeated silica gel column chromatography (granulate size 0.04-0.063 mm) using acetone /hexane 2:1 as eluent followed by chromatography on silica gel using methyl t.butyl ether/methanol/water 90:9:1 as eluent.
  • the mixture is stirred for 30 min. at -80°C, then a solution of 8g (6.6 mMol) cyclosporin C ([Thr] 2 -Ciclosporin) in 120 ml absolute THF is added through a syringe over 2 - 3 minutes.
  • the clear solution is stirred for a further hour at -80°C, then 2.06 ml methyl iodide is slowly added.
  • Ciclosporin as described in USP 4,396,542 and 4,798,823 is carried out using MeThr in the 4-position in place of MeLeu.
  • Ciclosporin as described in USP 4,396,542 and 4,798,823 is carried out using MeVal in the 4-position in place of MeLeu.
  • Table I gives examples of (1) the cyclophilin Binding Ratio (BR) of Active Compounds as measured in an ELISA assay and (2) the immunosuppressive activity of Active Compounds relative to Ciclosporin as measured in an MLR assay and expressed as a percentage of activity relative to Ciclosporin (Immunosuppressive Ratio or IR). Further explanation of the significance of these values and the methods for conducting these tests are set forth supra.
  • BR cyclophilin Binding Ratio
  • the Active Compounds are indicated both for the prevention of AIDS in asymptomatic HIV-positive patients and in the treatment of patients suffering from AIDS.
  • the administration of the Active Compound should reverse the T4-cell depletion associated with AIDS, induce regression of AIDS-related disorders, such as Kaposi's sarcoma, and reduce the liklihood of new opportunistic infections.
  • the invention provides a process for the treatment and the prevention of the acquired immunodeficiency syndrome and other disorders induced by the HIV-1 virus in a patient infected with said virus, comprising administering to said patient an effective amount of an Active Compound of the invention.
  • the Active Compound may be administered by any conventional route, in particular enterally, e.g. orally, for example in the form of solutions for drinking, tablets or capsules or parenterally, for example in the form of injectible solutions or suspensions.
  • enterally e.g. orally
  • an indicated daily dosage may be from 1 to 20 mg/kg, preferably from 3 to 10 mg/kg
  • oral route from 1 to 50 mg/kg, preferably from 7 to 20 mg/kg.
  • the toxicity of the Active Compounds is believed to be similar to that of Ciclosporin. As the Active Compounds are not immunosuppressive, certain side effects of Ciclosporin related to immunosuppression are avoided. Other side effects associated with Ciclosporin, however, particularly nephrotoxicity in long term use, may also be associated with the Active Compounds.
  • Preferred galenic formulations for the Active Compounds include those based on microemulsions as described in British Patent Application 2 222 770A, which include topical as well as oral forms; also oral and injectable forms obtained from solid solutions comprising a fatty acid saccharide monoester, e.g. saccharose monolaurate, as described in British Patent Application 2 209 671A.
  • Suitable unit dosage forms for oral administration comprise e.g. from 25 to 200mg Active Compound per dosage.

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Claims (12)

  1. Verwendung eines Cyclosporins zur Herstellung eines Arzneimittels zur Behandlung und Verhütung von AIDS und mit AIDS in Beziehung stehenden Störungen, dadurch gekennzeichnet, daß das Cyclosporin
    (i) an rekombinantes Humancyclophilin mit einem Bindungsverbältnis (BR) von weniger als 0,7 bindet, wobei BR der Logarithmus zur Basis 10 des Verhältnisses der IC50 von Cyclosporin zu der IC50 in einem Simultantest von Ciclosporin, gemessen in einem kompetitiven ELISA-Test, ist und
    (ii) eine Aktivität in der gemischten Lymphozytenreaktion von nicht mehr als 5% der von Ciclosporin hat.
  2. Verfahren zur Herstellung einer pharmazeutischen Zusammensetzung umfassend, daß man eine Verbindung der Formel I
    Figure 00310001
    worin
    W
    MeBmt, Dihydro-MeBmt oder 8'-Hydroxy-MeBmt ist;
    X
    αAbu, Val, Thr, Nva oder MeOThr ist;
    R
    Sar oder (D)-MeAla ist;
    Y
    MeLeu, γ-Hydroxy-MeLeu, MeIle, MeVal, MeThr, MeAla, MeaIle oder MeaThr ist;
    Z
    Val, Leu, MeVal oder MeLeu ist und
    Q
    MeLeu, γ-Hydroxy-MeLeu oder MeAla ist;
    mit dem Vorbehalt, daß, wenn Y MeLeu ist, dann entweder Z MeVal oder MeLeu ist oder W 8'-Hydroxy-MeBmt ist;
    mit einem pharmazeutisch annehmbaren Verdünnungsmittel oder Träger vereinigt.
  3. Verfahren zur Herstellung einer pharmazeutischen Zusammensetzung nach Anspruch 2, worin die Verbindung der Formel I eine Verbindung der Fomel I' ist
    Figure 00310002
    worin
    W'
    MeBmt oder Dihydro-MeBmt ist;
    X'
    αAbu oder Nva ist;
    Y'
    γ-Hydroxy-MeLeu, MeVal, MeThr oder MeIle ist und
    Z'
    Val oder MeVal ist;
  4. Verfahren zur Herstellung einer pharmazeutischen Zusammensetzung umfassend, daß man eine Verbindung ausgewählt aus:
    [Dihydro-MeBmt]1-[γ-Hydroxy-MeLeu]4-Ciclosporin
    [MeVal]4-Ciclosporin
    [MeIle]4-Ciclosporin
    [MeThr]4-Ciclosporin
    [γ-Hydroxy-MeLeu]4-Ciclosporin
    [Nva]2-[γ-Hydroxy-MeLeu]4-Ciclosporin
    [γ-Hydroxy-MeLeu]4-[γ-Hydroxy-MeLeu]6-Ciclosporin
    [MeVal]5-Ciclosporin
    [MeOThr]2-[(D)MeAla]3-[MeVal]5-Ciclosporin
    [8'-Hydroxy-MeBmt]1-Ciclosporin und
    [γ-Hydroxy-MeLeu]9-Ciclosporin
    mit einem pharmazeutisch annehmbaren Verdünnungsmittel oder Träger vereinigt.
  5. Verwendung einer Verbindung der Formel I oder I', wie in Anspruch 2 oder Anspruch 3 beschrieben oder einer Verbindung ausgewählt aus den in Anspruch 4 aufgeführten Cyclosporinen zur Herstellung eines Arzneimittels zur Behandlung und Verhütung von AIDS und mit AIDS in Beziehung stehenden Störungen.
  6. Verfahren zur Herstellung von [MeIle]4-Ciclosporin umfassend die Stufe, daß man einen [MeIle]4-Ciclosporin produzierenden Stamm von Tolypocladium inflatum Gams in einem Nährmedium züchtet und das Produkt aus der Fermentationsbrühe isoliert.
  7. Verfahren nach Anspruch 6, worin der [MeIle]4-Ciclosporin produzierende Stamm Tolypocladium inflatum Gams DSM 6627 ist.
  8. Reine Kultur des Pilzstamms DSM 6627.
  9. Verfahren zur Herstellung von Cyclosporinen, die einen oder mehrere γ-Hydroxy-MeLeu-Reste haben, umfassend, die Stufen, daß man den Pilzstamm DSM 6182 in einem Nährmedium züchtet, ein Cyclosporin zugibt, das einen oder mehrere MeLeu-Reste hat, und das Produkt aus der Fermentationsbrühe isoliert.
EP91810841A 1990-11-02 1991-10-30 Zyklosporine Expired - Lifetime EP0484281B2 (de)

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GB909023859A GB9023859D0 (en) 1990-11-02 1990-11-02 Chemical products
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GB909023971A GB9023971D0 (en) 1990-11-05 1990-11-05 New use of a cyclosporin derivative
GB909023972A GB9023972D0 (en) 1990-11-05 1990-11-05 New use of a cyclosporin derivative
GB9023972 1990-11-05
GB9023971 1990-11-05
GB909023970A GB9023970D0 (en) 1990-11-05 1990-11-05 New use of a cyclosporin derivative
GB9023970 1990-11-05
GB919116836A GB9116836D0 (en) 1991-08-05 1991-08-05 Organic compounds
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7696166B2 (en) 2006-03-28 2010-04-13 Albany Molecular Research, Inc. Use of cyclosporin alkyne/alkene analogues for preventing or treating viral-induced disorders
US7696165B2 (en) 2006-03-28 2010-04-13 Albany Molecular Research, Inc. Use of cyclosporin alkyne analogues for preventing or treating viral-induced disorders
US9200038B2 (en) 2010-12-15 2015-12-01 Ciclofilin Pharmaceuticals Corp. Cyclosporine analogue molecules modified at amino acid 1 and 3

Families Citing this family (78)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0624093A1 (de) * 1992-01-28 1994-11-17 KARPAS, Abraham Verwendung einer Verbindung zur Herstellung eines Arzneimittel zur Behandlung einer HIV-Infektion
GB9204466D0 (en) * 1992-03-02 1992-04-15 Sandoz Ltd Improvements in or relating to organic compounds
ES2065273B1 (es) * 1993-05-25 1995-09-16 Biogal Gyogyszergyar Procedimiento para la purificacion de ciclosporina a.
US5948693A (en) * 1994-09-01 1999-09-07 Wisconsin Alumni Research Foundation Solid phase synthesis of immunosuppressive agents
US5639852A (en) * 1994-09-01 1997-06-17 Wisconsin Alumni Research Foundation Immunostimulatory agents
US6696413B2 (en) 1995-06-16 2004-02-24 Hexal Ag Pharmaceutical preparation with cyclosporin A
KR100441220B1 (ko) * 1995-07-17 2005-02-24 체-헴 아게 항-hiv효과를갖는사이클로스포린유도체
JP3089350B2 (ja) * 1995-11-20 2000-09-18 ギルフォード ファーマシューティカルズ インコーポレイテッド シクロフィリンロタマーゼ活性の阻害剤
JP2000510097A (ja) * 1996-03-12 2000-08-08 ザ ピコワー インスティテュート フォー メディカル リサーチ 宿主細胞シクロフィリンレセプター活性を妨げることによるｈｉｖ感染の治療
CN1130373C (zh) * 1996-09-13 2003-12-10 诺瓦蒂斯有限公司 [3'－脱氧－3'－氧代－MeBmt]'环孢菌素制备方法
FR2757520B1 (fr) * 1996-12-24 1999-01-29 Rhone Poulenc Rorer Sa Derive de cyclosporine, sa preparation et les compositions pharmaceutiques qui le contiennent
FR2757522B1 (fr) * 1996-12-24 1999-01-29 Rhone Poulenc Rorer Sa Derives de cyclosporine, leur preparation et les compositions pharmaceutiques qui les contiennent
FR2757521B1 (fr) * 1996-12-24 1999-01-29 Rhone Poulenc Rorer Sa Nouveaux derives de cyclosporine, leur preparation et les compositions pharmaceutiques qui les contiennent
FR2762843B1 (fr) * 1997-04-30 1999-12-10 Rhone Poulenc Rorer Sa Nouveaux derives de cyclosporine, leur preparation et les compositions pharmaceutiques qui les contiennent
US20030220234A1 (en) * 1998-11-02 2003-11-27 Selvaraj Naicker Deuterated cyclosporine analogs and their use as immunodulating agents
ES2256959T3 (es) 1997-10-08 2006-07-16 Isotechnika,Inc. Analogos de ciclosporina deuterados y no deuterados y su uso como agentes inmunomoduladores.
ZA99981B (en) * 1998-02-17 2000-08-08 Du Pont Pharm Co Oral liquid formulations of benzoxazinones HIV reverse transcriptase inhibitors.
GB9811854D0 (en) * 1998-06-02 1998-07-29 Ciba Geigy Ag Organic compounds
FR2780061B1 (fr) 1998-06-22 2001-09-07 Rhone Poulenc Rorer Sa Nouveau procede de preparation de derives de cyclosporine
MXPA00013019A (es) 1998-07-01 2003-07-14 Debiopharm Sa Ciclosporina novedosa con perfil de actividad mejorado.
AU769429C (en) 1998-12-30 2004-10-28 Dexcel Limited Dispersible concentrate for the delivery of cyclosporin
US6521595B1 (en) * 1999-11-19 2003-02-18 Lg Chemical, Ltd. Nonimmunosuppressive [γ-hydroxy-methylleucine4] cyclosporin A, hair growth stimulator and external composition for skin using the same
US7732404B2 (en) 1999-12-30 2010-06-08 Dexcel Ltd Pro-nanodispersion for the delivery of cyclosporin
IL158385A0 (en) * 2001-04-20 2004-05-12 Debiopharm Sa Modified cyclosporin which can be used as a pro-drug and use thereof
KR100695611B1 (ko) * 2001-05-17 2007-03-14 주식회사 엘지생활건강 [감마 히드록시 엔-메틸 엘-루신4] 사이클로스포린유도체를 유효성분으로 하는 모발 성장 촉진제
CA2461730C (en) * 2001-10-19 2012-05-15 Isotechnika Inc. Novel cyclosporin analog microemulsion preconcentrates
US6998385B2 (en) * 2001-10-19 2006-02-14 Isotechnika Inc. Cyclosporine analogue mixtures and their use as immunomodulating agents
EP1439853A2 (de) * 2001-10-25 2004-07-28 Hans Will Mittel zur hemmung der synthese von virusproteinen
US7108988B2 (en) * 2001-11-02 2006-09-19 The J. David Gladstone Institutes Methods of identifying agents for inhibiting lentivirus replication
AU2004222306A1 (en) * 2003-03-17 2004-09-30 Albany Molecular Research, Inc. Novel cyclosporins
GB0320638D0 (en) 2003-09-03 2003-10-01 Novartis Ag Organic compounds
US20050059583A1 (en) 2003-09-15 2005-03-17 Allergan, Inc. Methods of providing therapeutic effects using cyclosporin components
RU2006139004A (ru) * 2004-04-08 2008-05-20 Новартис АГ (CH) Применение циклоспоринов для лечения церебральной ишемии и повреждения головного и спинного мозга
JP2008512351A (ja) * 2004-07-13 2008-04-24 ノバルティス アクチエンゲゼルシャフト アルツハイマー病を処置するためのサイクロスポリン
RU2394589C2 (ru) 2004-07-14 2010-07-20 Новартис Аг Применение комбинации циклоспорина и пэгилированного интерферона для лечения гепатита с (hcv)
KR100597309B1 (ko) 2004-09-17 2006-07-05 주식회사 핸슨바이오텍 세베키아 베니하나를 이용한 [감마 히드록실메틸루신4] 사이클로스포린 a의 제조방법
JP2008514701A (ja) * 2004-09-29 2008-05-08 エーエムアール テクノロジー インコーポレイテッド シクロスポリンアルキン類似体およびそれらの薬学的使用
WO2006039164A2 (en) * 2004-09-29 2006-04-13 Amr Technology, Inc. Novel cyclosporin analogues and their pharmaceutical uses
ES2373450T3 (es) * 2004-10-01 2012-02-03 Scynexis, Inc. Derivados de ciclosporina sustituidos con 3-éter y 3-tioéter para el tratamiento y la prevención de infección por hepatitis c.
US7196161B2 (en) * 2004-10-01 2007-03-27 Scynexis Inc. 3-ether and 3-thioether substituted cyclosporin derivatives for the treatment and prevention of hepatitis C infection
EP1812037A4 (de) * 2004-10-06 2009-11-11 Amr Technology Inc Neue cyclosporin-alkyne und ihre nutzung als pharmazeutishe mittel
US7135455B2 (en) * 2004-11-15 2006-11-14 Allergan, Inc Methods for the therapeutic use of cyclosporine components
US7151085B2 (en) * 2004-11-15 2006-12-19 Allergan, Inc. Therapeutic methods using cyclosporine components
KR100777488B1 (ko) 2004-12-15 2007-11-28 주식회사 핸슨바이오텍 세베키아 베니하나 (Sebekia benihana)배양물로부터 감마-히드록실메틸루신4 사이클로스포린 A를 효과적이고 선택적으로 회수하는 방법
NZ555142A (en) * 2004-12-23 2010-03-26 Novartis Ag Compounds for flaviviridae treatment
MX2007007779A (es) * 2004-12-23 2007-08-14 Novartis Ag Composiciones para el tratamiento de infeccion de hepatitis c.
ATE498630T1 (de) * 2005-09-30 2011-03-15 Scynexis Inc Arylalkyl- und heteroarylalkyl-derivate von cyclosporin a bei der behandlung und vorbeugung einer virusinfektion
EP2007789B1 (de) 2006-04-11 2015-05-20 Novartis AG Spirozyklische HCV/HIV-Hemmer und ihre Verwendung
US8188052B2 (en) 2006-05-19 2012-05-29 Scynexis, Inc. Method for the treatment and prevention of ocular disorders
CN101502196A (zh) * 2006-06-02 2009-08-05 克洛德·安妮·佩里西恩 激活电子的管理
WO2008069917A2 (en) * 2006-11-20 2008-06-12 Scynexis, Inc. Novel cyclic peptides
US20080255038A1 (en) * 2007-04-11 2008-10-16 Samuel Earl Hopkins Pharmaceutical compositions
EP2195009B1 (de) * 2007-09-26 2014-07-30 Oregon Health and Science University Zyklische undekapeptide und derivate als therapien für multiple sklerose
WO2009148615A1 (en) * 2008-06-06 2009-12-10 Scynexis, Inc. Cyclosporin analogs and their use in the treatment of hcv infections
WO2010002428A2 (en) * 2008-06-06 2010-01-07 Scynexis, Inc. Novel macrocyclic peptides
MX2011001152A (es) 2008-07-30 2011-06-09 Isotechnika Pharma Inc Moleculas de analogo de ciclosporina no-inmunesupresoras.
CN102307892A (zh) 2008-12-31 2012-01-04 西尼克斯公司 环孢菌素a的衍生物
US11304960B2 (en) 2009-01-08 2022-04-19 Chandrashekar Giliyar Steroidal compositions
US8481483B2 (en) * 2009-02-19 2013-07-09 Enanta Pharmaceuticals, Inc. Cyclosporin analogues
US8512690B2 (en) 2009-04-10 2013-08-20 Novartis Ag Derivatised proline containing peptide compounds as protease inhibitors
US20110182850A1 (en) 2009-04-10 2011-07-28 Trixi Brandl Organic compounds and their uses
GB0909754D0 (en) * 2009-06-05 2009-07-22 Magnani Mauro Drug delivery systems
CN102811998B (zh) * 2009-12-21 2016-03-30 国家健康与医学研究院（Inserm） 新的亲环素抑制剂及其用途
CA2785978A1 (en) 2009-12-30 2011-07-07 Scynexis, Inc. Cyclosporine analogues
US9217015B2 (en) 2010-07-16 2015-12-22 S&T Global Inc. Cyclosporin derivatives for the treatment and prevention of a viral infection
WO2012021796A2 (en) 2010-08-12 2012-02-16 S&T Global, Inc. Novel cyclosporin derivatives for the treatment and prevention of a viral infection
EP2624826B1 (de) 2010-10-08 2018-07-18 Novartis AG Zusammensetzungen enthaltend vitamin e und sulfamide mit ns3 hemmender wirkung
US9034858B2 (en) 2010-11-30 2015-05-19 Lipocine Inc. High-strength testosterone undecanoate compositions
US20180153904A1 (en) 2010-11-30 2018-06-07 Lipocine Inc. High-strength testosterone undecanoate compositions
US9358241B2 (en) 2010-11-30 2016-06-07 Lipocine Inc. High-strength testosterone undecanoate compositions
US9890198B2 (en) 2010-12-03 2018-02-13 S&T Global Inc. Cyclosporin derivatives and uses thereof
US20120148675A1 (en) 2010-12-10 2012-06-14 Basawaraj Chickmath Testosterone undecanoate compositions
US20120253007A1 (en) * 2011-03-28 2012-10-04 The Government Of The United States Of America, As Represented By The Secretary Of The Navy Synthesis of Cyclosporin H
US20140205566A1 (en) 2012-11-30 2014-07-24 Novartis Ag Cyclic nucleuoside derivatives and uses thereof
WO2016033556A1 (en) 2014-08-28 2016-03-03 Lipocine Inc. BIOAVAILABLE SOLID STATE (17-β)-HYDROXY-4-ANDROSTEN-3-ONE ESTERS
US20170246187A1 (en) 2014-08-28 2017-08-31 Lipocine Inc. (17-ß)-3-OXOANDROST-4-EN-17-YL TRIDECANOATE COMPOSITIONS AND METHODS OF THEIR PREPARATION AND USE
US11559530B2 (en) 2016-11-28 2023-01-24 Lipocine Inc. Oral testosterone undecanoate therapy
CN111449050A (zh) 2019-01-20 2020-07-28 睿诺医疗科技（上海）有限公司 环孢菌素类似物及其用途

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4914188A (en) † 1987-11-16 1990-04-03 Merck & Co., Inc. Novel 6-position cyclosporin analogs as non-immunosuppressive antagonists of cyclosporin binding to cyclophilin

Family Cites Families (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2455859C2 (de) 1973-12-06 1983-12-15 Sandoz-Patent-GmbH, 7850 Lörrach Das Antibiotikum Cyclosporin A (S 7481/F-1), seine Herstellung und Verwendung
US4304855A (en) * 1977-05-05 1981-12-08 The Upjohn Company Allylic methyl-hydroxylated novobiocins
CH667274A5 (de) * 1984-03-23 1988-09-30 Sandoz Ag Cyclosporine, ihre herstellung und diese enthaltende pharmazeutische zusammensetzungen.
EP0194972B1 (de) * 1985-03-11 1992-07-29 Sandoz Ag Cyclosporine
US4814323A (en) * 1986-03-25 1989-03-21 Andrieu J M Process for the treatment and the prevention of AIDS and other disorders induced by the LAV/HTLV III virus
EP0283801A3 (de) * 1987-03-27 1990-05-30 Abbott Laboratories Fluoreszenz-Polarisations-Test für Cyclosporin A und Metaboliten und verwandte Immunogene und Antikörper
US4798823A (en) * 1987-06-03 1989-01-17 Merck & Co., Inc. New cyclosporin analogs with modified "C-9 amino acids"
DE3888357T2 (de) * 1987-06-22 1994-09-15 Merck & Co Inc Cyclosporin-Derivate, die eine modifizierte Aminosäure auf Stellung 8 tragen.
GB8717300D0 (en) * 1987-07-22 1987-08-26 Nat Res Dev Cyclosporins
US4981799A (en) * 1987-08-21 1991-01-01 Takeda Chemical Industries, Ltd. Acylamino acid racemase, production and use thereof
US5081024A (en) * 1988-09-05 1992-01-14 Nissan Chemical Industries, Ltd. Process for producing optically active amino acids
GB2227244A (en) * 1989-01-19 1990-07-25 Merck & Co Inc Immunosuppressive fluorinated cyclosporin analogs
US5122511A (en) * 1990-02-27 1992-06-16 Merck & Co., Inc. Immunosuppressive cyclosporin analogs with modified amino acids at position-8

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4914188A (en) † 1987-11-16 1990-04-03 Merck & Co., Inc. Novel 6-position cyclosporin analogs as non-immunosuppressive antagonists of cyclosporin binding to cyclophilin

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Klatzmann D.et al, C.R. Acad.Sci.Paris 303 III(9), (1986), 343-48 †
Quesniaux V.F.J.et al, Eur.J.of Immunol. 17 (1987), 1359-65 †
Sigal N.H.et al, J.Exp.Med.173 (1991), 619-28 †

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7696166B2 (en) 2006-03-28 2010-04-13 Albany Molecular Research, Inc. Use of cyclosporin alkyne/alkene analogues for preventing or treating viral-induced disorders
US7696165B2 (en) 2006-03-28 2010-04-13 Albany Molecular Research, Inc. Use of cyclosporin alkyne analogues for preventing or treating viral-induced disorders
US9200038B2 (en) 2010-12-15 2015-12-01 Ciclofilin Pharmaceuticals Corp. Cyclosporine analogue molecules modified at amino acid 1 and 3

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ATE148469T1 (de) 1997-02-15
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US5767069A (en) 1998-06-16
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MY134806A (en) 2007-12-31
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CS329791A3 (en) 1992-05-13
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US6255100B1 (en) 2001-07-03
AU8692391A (en) 1992-05-07
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PT99410B (pt) 1999-04-30
EP0484281A2 (de) 1992-05-06
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IL99912A0 (en) 1992-08-18
HU212674B (en) 1996-09-30
GR3035323T3 (en) 2001-04-30
AU649277B2 (en) 1994-05-19
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FI111730B (fi) 2003-09-15
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SA92120344B1 (ar) 2004-01-24
GR3022592T3 (en) 1997-05-31
CZ280909B6 (cs) 1996-05-15
IE913824A1 (en) 1992-05-22
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CY2159B1 (en) 2002-08-23
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IL99912A (en) 1996-09-12
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MX9101869A (es) 1993-04-01
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